Assessing the amount of glaucomatous damage is the first step toward the correct management of glaucoma. This is usually estimated by observation of structures affected by glaucoma (RNFL and optic nerve head) and by testing visual function (VF test). Periodic assessment is the way to establish the rate of progression. It is of fundamental importance to know the way in which damage to specific structures affects visual function.
In this study, an objective quantitative measurement of RNFL thickness, as measured by the GDx, was correlated with a quantitative measurement of VF that depends on subjective responses of a patient. The relationship between RNFL thickness, as measured by the scanning laser polarimeter, and VF sensitivity compares well with structure/function correlation studies reported in the literature
6 25 28 29 The global and sectoral relationships were significantly greater when corneal birefringence was compensated for each eye individually with the VCC setting than when the FCC was used. This is explained by the error in measurements introduced by erroneously compensated corneal birefringence when using the FCC in eyes where the axis and magnitude of birefringence differ from population mode values.
30 The device used in this study was a prototype, but operating on the same principles as the commercially available device that has since been made available. A study, similar to that reported in this article, using the commercially available device identified a curvilinear dB/RNFL thickness relationship and a linear 1/L/RNFL thickness relationship (Lemij HG, et al.
IOVS 2003;44:ARVO E-Abstract 978).
Differential light sensitivity (DLS) is measured in VF testing in a logarithmic (dB) scale because this facilitates the appreciation of the wide range in retinal sensitivity found in normal and diseased eyes, and the psychometric function (frequency of seeing curve) conventionally is modeled in logarithmic units. However, a previous study assessed the relationship between ganglion cell number and DLS, and revealed a linear relationship when DLS was represented in the 1/L scale and a curvilinear relationship when DLS was represented in the dB scale.
7 These findings are consistent with those of other studies correlating neuroretinal rim area by planimetry and scanning laser tomography with VF loss.
5 8 9 10 In these studies, a curvilinear relationship between neuroretinal rim and dB DLS was found. Further support comes from a study that related electrophysiological, psychophysical, and anatomic measurements in glaucomatous patients by using pattern electroretinogram (PERG), perimetry, and retinal tomography.
6 This study showed that the relationship between DLS and both PERG amplitude and neuroretinal rim area was curvilinear in the dB scale, and linear in the 1/L DLS scale. These results are consistent with the present study and indicate that, if the true underlying relationship between structure and function is curvilinear with the dB scale, and a linear model of dB functional progression is assumed, then one will underestimate the rate of change at near normal values, giving the impression of a functional reserve. It also results in the overestimation of the rate of change at more advanced stages of VF loss. The findings of this study support the hypothesis that there is no ganglion cell functional reserve but a continuous structure to function relationship, and that the impression of a functional reserve results, at least in part, from the logarithmic (dB) scaling of the VF.
Selection bias has the potential to affect the apparent structure/function relationship. In this study, glaucoma was defined on the basis of VF loss, without requirements for structural damage. However, patients were recruited from glaucoma clinics, and an assessment of structural damage usually forms a part of the diagnostic procedure. This is likely to strengthen the discovered structure/function relationship, though is unlikely to affect its pattern. Because the selection criteria were based on VF damage, it is likely that patients with VF loss, but healthier optic nerves, are included. The opposite group, patients with glaucomatous optic discs but no VF loss, were excluded. It is possible that this group of patients would exhibit functional reserve and this possibility requires further study. The effect of this selection bias would work in the opposite direction to the findings of this study, that structural damage appears more advanced than dB VF loss in the early stages of glaucoma.
The analysis in this study assumed the same structure/function relationship in the normal and glaucoma subjects, and visual inspection of the plots
(Fig. 3) suggests that all subjects are part of the same distribution. However, further work is required to confirm or refute this assumption.
Visual field tests are a way of estimating loss of function associated with ganglion cell drop-out, and do not provide a direct measure of ganglion cell function. In previous studies, where relationships between VF and rim area were sought to describe the structure/function relationship,
6 9 the function of ganglion cells was related to an anatomic structure (the neuroretinal rim), which comprises axons of ganglion cells and other structures such as blood vessels and glial cells. In this study, ganglion cell function correlated with RNFL thickness (related more directly to ganglion cell axon numbers). Because scanning laser polarimetry measures birefringence of the tissue in the peripapillary area, and it is believed that birefringence arises principally from microtubules within the ganglion cell axons,
15 this technology may be more appropriate for structure/function correlation and result in higher correlations.
No structure/function relationship was found in the temporal segment; there are a number of possible explanations for this. No adjustment for spatial summation in the central field was made. As the size of the stimuli remains unchanged across the VF, at early stages of damage this results in less change in the DLS in the central (within 15°of fixation), compared with peripheral, VF locations. In the temporal sector, there was a wide range of RNFL thickness measurements but no consistent associated change in VF sensitivity. The lack of relationship could also be explained by an apparent variation of tissue birefringence around the optic nerve head due to underlying structural differences among nerve bundles that serve different retinal regions (Huang X, et al. IOVS 2003;44:ARVO E-Abstract 3363).
There appeared to be an offset of RNFL measurements below 20 μm, and so the RNFL never appeared to be zero. It is not clear whether this was due to inaccuracies in measuring a thin RNFL or another source of retardation arising from unrecognized structures that had not previously been considered.
The results obtained in this study regarding the decline in RNFL thickness with age of 0.25% per year are consistent with previous imaging
31 and histologic studies,
32 33 and provide support to the notion that the GDx VCC measures ganglion cell axons or a correlate of these axons.
8 9 Histologic studies have reported an age-related decline in optic nerve axon count, with the estimated rate of decline ranging from around 0.36%
33 to 0.62%
32 per year, similar to the rate of RNFL loss found in this study.
In summary, the strength of the structure/function relationships compared well with previous reports in the literature. The relationships were curvilinear with the dB scale and linear with the 1/L scale, and were much stronger with VCC than with FCC RNFL thickness measurements. Functional measurements in a linear scale should reflect disease progression more accurately and correlate better with structural measurements of disease progression. This study contributes to a better understanding of the relationship between structure and function, and may lead to an improved staging of the disease by means of a more appropriate measurement scale.
The authors thank Tuan A. Ho for editorial help with the manuscript.